Dry powder inhaler formulations comprising surface-modified particles with anti-adherent additives

ABSTRACT

The present invention is concerned with a refinement of the processing of particles that are to form a dry powder formulation which is to be administered to the lung using a dry powder inhaler (DPI) device. In particular, the present invention provides the processing of particles of active material and particles of carrier material in the presence of additive material to provide a powder composition which exhibits excellent powder properties and which is economical to produce.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/085,200 filed Apr. 12, 2011, which is a continuation of U.S.application Ser. No. 11/791,385 filed Jul. 5, 2007, now abandoned whichis a United States national stage of International Application No.PCT/GB2005/050211, filed Nov. 23, 2005, which was published asInternational Publication No. WO 2006/056812, and which claims benefitof United Kingdom Application No. 0425758.0 filed, Nov. 23, 2004, theentire contents of which are hereby expressly incorporated herein byreference thereto.

FIELD OF THE INVENTION

The present invention is concerned with a refinement of the processingof particles that are to form a dry powder formulation which is to beadministered to the lung, for example using a dry powder inhaler (DPI)device. In particular, the present invention provides the processing ofparticles of active material and particles of carrier material in thepresence of additive material to provide a powder composition whichexhibits excellent powder properties and which is economical to produce.

BACKGROUND OF THE INVENTION

Inhalation represents a very attractive, rapid and patient-friendlyroute for the delivery of systemically acting drugs, as well as fordrugs that are designed to act locally on the lungs themselves. It isparticularly desirable and advantageous to develop technologies fordelivering drugs to the lungs in a predictable and reproducible manner.

The key features which make inhalation an exciting drug delivery routeare: rapid speed of onset; improved patient acceptance and compliancefor a non-invasive systemic route; reduction of side effects; productlife cycle extension; improved consistency of delivery; access to newforms of therapy, including higher doses, greater efficiency andaccuracy of targeting; and direct targeting of the site of action forlocally administered drugs, such as those used to treat lung diseasessuch as asthma, COPD, CF or lung infections.

However, the powder technology behind successful dry powders and DPIproducts remains a significant technical hurdle to those wishing tosucceed with this route of administration and to exploit the significantproduct opportunities. Any formulation must have suitable flowproperties, not only to assist in the manufacture and metering of thepowders, but also to provide reliable and predictable resuspension andfluidisation, and to avoid excessive retention of the powder within thedispensing device.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the microporosity of various types of lactose particles asmeasured using the Cooker SA 3100 BET system as defined by pore diameter(nm) versus cumulative percentage.

FIG. 2, also noted as Table 1, shows the Hosokawa Powder Tester Resultsfor Sorbolac 400 (Mechanofused).

FIG. 3, also noted as Table 2, shows the Hosokawa Powder Tester Resultsfor Extra Fine Lactose.

FIG. 4, also noted as Table 3, shows the Hosokawa Powder Tester Resultsfor Sorbolac 400 (Cyclomixed).

FIG. 5, also noted as Table 4, shows the Hosokawa Powder Tester Resultsfor Micronised Lactose (Model Drug).

FIG. 6, also noted as Table 5, shows the Hosokawa Powder Tester Resultsfor SU003 (Conventional “Large” Carrier).

FIG. 7 shows the zeta potential of Lactose. Lactose/Magnesium Stearatethat has been Turbula-blended and Lactose/Magnesium Stearate that hasbeen mechanofused.

DETAILED DESCRIPTION OF THE INVENTION

The drug particles or particles of pharmaceutically active material(also referred to herein as “active” particles) in the resuspendedpowder must aerosolise into an ultra-fine aerosol so that they can betransported to the appropriate target area within the lung. Typically,for lung deposition, the active particles have a diameter of less than10 μms, frequently 0.1 to 7 μm, 0.1 to 5 μm, or 0.5 to 5 μm.

For formulations to reach the deep lung or the blood stream viainhalation, the active agent in the formulation must be in the form ofvery fine particles, for example, having a mass median aerodynamicdiameter (MMAD) of less than 10 μm. It is well established thatparticles having an MMAD of greater than 10 μm are likely to impact onthe walls of the throat and generally do not reach the lung. Particleshaving an MMAD in the region of 5 to 2 μm will generally be deposited inthe respiratory bronchioles whereas particles having an MMAD in therange of 3 to 0.05 μm are likely to be deposited in the alveoli and tobe absorbed into the bloodstream.

Preferably, for delivery to the lower respiratory tract or deep lung,the MMAD of the active particles is not more than 10 μm, and preferablynot more than more preferably not more than 3 μm, and may be less than 2μm, less than 1.5 μm or less than 1 μm. Especially for deep lung orsystemic delivery, the active particles may have a size of 0.1 to 3 μmor 0.1 to 2 μm.

Ideally, at least 90% by weight of the active particles in a dry powderformulation should have an aerodynamic diameter of not more than 10 μm,preferably not more than 5 μm, more preferably not more than 3 μm, notmore than 2.5 μm, not more than 2.0 μm, not more than 1.5 μm, or evennot more than 1.0 μm.

When dry powders are produced using conventional processes, the activeparticles will vary in size, and often this variation can beconsiderable. This can make it difficult to ensure that a high enoughproportion of the active particles are of the appropriate size foradministration to the correct site. It is therefore desirable to have adry powder formulation wherein the size distribution of the activeparticles is as narrow as possible. For example, the geometric standarddeviation of the active particle aerodynamic or volumetric sizedistribution (σg), is preferably not more than 2, more preferably notmore than 1.8, not more than 1.6, not more than 1.5, not more than 1.4,or even not more than 1.2. This will improve dose efficiency andreproducibility.

Fine particles, that is, those with an MMAD of less than 101. μm andsmaller, tend to be increasingly thermodynamically unstable as theirsurface area to volume ratio increases, which provides an increasingsurface free energy with this decreasing particle size, and consequentlyincreases the tendency of particles to agglomerate and the strength ofthe agglomerate. In the inhaler, agglomeration of fine particles andadherence of such particles to the walls of the inhaler are problemsthat result in the fine particles leaving the inhaler as large, stableagglomerates, or being unable to leave the inhaler and remaining adheredto the interior of the inhaler, or even clogging or blocking theinhaler.

The uncertainty as to the extent of formation of stable agglomerates ofthe particles between each actuation of the inhaler, and also betweendifferent inhalers and different batches of particles, leads to poordose reproducibility. Furthermore, the formation of agglomerates meansthat the MMAD of the active particles can be vastly increased, withagglomerates of the active particles not reaching the required part ofthe lung.

These micron to submicron particle sizes required for deep lung orsystemic delivery lead to the problem that the respirable activeparticles tend to be highly cohesive, which means they generally exhibitpoor flowability and poor aerosolisation.

To overcome the highly cohesive nature of such respirable activeparticles, formulators have, in the past, included larger carrierparticles of an inert excipient in powder formulations, in order to aidboth flowability and drug aerosolisation. Relatively large carrierparticles have a beneficial effect on the powder formulations because,rather than sticking to one another, the fine active particles tend toadhere to the surfaces of the larger carrier particles whilst in theinhaler device. The active particles are supposed to release from thecarrier particle surfaces and become dispersed upon actuation of thedispensing device, to give a fine suspension which may be inhaled intothe respiratory tract. In general, it has been considered that thecarrier particles should preferably have a mass median aerodynamicdiameter (MMAD) of at least about 90 μm, and in general terms shouldpreferably have a mass median aerodynamic diameter (MMAD) of greaterthan 40 μm, and not less than 20 μm.

However, whilst the addition of relatively large carrier particles doestend to improve the powder properties, it also has the effect ofdiluting the drug, usually to such an extent that 95% or more by totalweight of the formulation is carrier. Relatively large amounts ofcarrier are required in order to have the desired effect on the powderproperties because the majority of the fine or ultra-fine activeparticles need to adhere to the surfaces of the carrier particles,otherwise the cohesive nature of the active particles still dominatesthe powder and results in poor flowability. The surface area of thecarrier particles available for the fine particles to adhere todecreases with increasing diameter of the carrier particles. However,the flow properties tend to become worse with decreasing diameter.Hence, there is a need to find a suitable balance in order to obtain asatisfactory carrier powder. An additional consideration is that one canget segregation if too few carrier particles are included, which isextremely undesirable.

An additional major problem experienced by formulators is thevariability in surface properties of drug and excipient particles. Eachactive agent powder has its own unique inherent stickiness or surfaceenergy, which can range tremendously from compound to compound. Further,the nature of the surface energies can change for a given compounddepending upon how it is processed. For example, jet milling isnotorious for generating significant variations in surface propertiesbecause of the aggressive nature of the collisions it employs. Suchvariations can lead to increased surface energy and increasedcohesiveness and adhesiveness.

Even in highly regular, crystalline powders, the short range van derWaals forces (which include fixed dipole and similar fixed chargerelated forces and which depend on the chemistry of the functionalgroups exposed on the surface of the particles) can lead to highlycohesive and adhesive powders.

Solutions to some of the problems touched upon above are already known.For example, flow problems associated with larger amounts of finematerial (for example, in powder formulations including relatively highproportions (such as up to from 5 to 20% by total weight of theformulation) of fine lactose or drug and fine lactose) may be overcomeby use of a large fissured lactose as carrier particles, as discussed inearlier patent applications published as WO 01/78694, WO 01/78695 and WO01/78696.

In order to improve the properties of powder formulations, and inparticular to improve the flowability and dispersibility of theformulation, dry powder formulations often include additive materialswhich are intended to reduce the cohesion between the fine particles inthe dry powder formulation. It is thought that the additive materialinterferes with the weak bonding forces between the small particles,helping to keep the particles separated and reducing the adhesion ofsuch particles to one another, to other particles in the formulation ifpresent and to the internal surfaces of the inhaler device. Whereagglomerates of particles are formed, the addition of particles ofadditive material decreases the stability of those agglomerates so thatthey are more likely to break up in the turbulent air stream created onactuation of the inhaler device, where upon the particles are expelledfrom the device and inhaled.

In the prior art, dry powder formulations are discussed which includeadditive material (for example in the form of distinct particles of asize comparable to that of the fine active particles). In someembodiments, the additive material may be applied to and form a coating,generally a discontinuous coating, on the active particles or on anycarrier particles.

Preferably, the additive material is an anti-adherent material and itwill tend to reduce the cohesion between particles and will also preventfine particles becoming attached to surfaces within the inhaler device.Advantageously, the additive material is an anti-friction agent orglidant and will give the powder formulation better flow properties inthe inhaler. The additive materials used in this way may not necessarilybe usually referred to as anti-adherents or anti-friction agents, butthey will have the effect of decreasing the cohesion between theparticles or improving the flow of the powder. As such, the additivematerials are sometimes referred to as force control agents (FCAs) andthey usually lead to better dose reproducibility and higher fineparticle fractions (FPFs).

Therefore, an additive material or FCA, as used herein, is a materialwhose presence on the surface of a particle can modify the adhesive andcohesive surface forces experienced by that particle, in the presence ofother particles and in relation to the surfaces that the particles areexposed to. In general, its function is to reduce both the adhesive andcohesive forces.

The reduced tendency of the particles to bond strongly, either to eachother or to the device itself, not only reduces powder cohesion andadhesion, but can also promote better flow characteristics. This leadsto improvements in the dose reproducibility because it reduces thevariation in the amount of powder metered out for each dose and improvesthe release of the powder from the device. It also increases thelikelihood that the active material which does leave the device willreach the lower lung of the patient.

It is favourable for unstable agglomerates of particles to be present inthe powder when it is in the inhaler device. For a powder to leave aninhaler device efficiently and reproducibly, it is generally acceptedthat the particles should ideally be large, preferably larger than about40 μm. Such a powder may be in the form of either individual particleshaving a size of about 40 μm or larger and/or agglomerates of finerparticles, the agglomerates having a size of about 40 μm or larger. Theagglomerates formed can have a size of as much as about 1000 μm and,with the addition of the additive material, those agglomerates are morelikely to be broken down efficiently in the turbulent airstream createdon inhalation. Therefore, the formation of unstable or “soft”agglomerates of particles in the powder may be favoured compared with apowder in which there is substantially no agglomeration. Such unstableagglomerates are retained whilst the powder is inside the device but arethen disrupted and broken up when the powder is dispensed.

The use of additive materials in this manner is disclosed in two earlierpatent applications, published as WO 96/23485 and WO 97/03649.

It is also known that intensive co-milling of micronised drug particleswith additive material may be carried out in order to produce compositeparticles. This co-micronisation can improve dispersibility, asdisclosed in the earlier patent application published as WO 02/43701. Inaddition, the earlier application published as WO 02/00197 discloses theintensive co-milling of fine particles of excipient material withadditive material, to create composite excipient particles to which fineactive particles and, optionally, coarse carrier particles may be added.This co-micronisation of fine excipient particles and additive materialhas also been shown to improve dispersibility.

Whilst the various disclosures in the prior art of the use of additivematerials as force control agents do indicate improvements in powderproperties (such as the dispersibility and flow) as a result of theaddition of the additive material, the known powders and processingmethods fail to provide the maximum effect possible with the optimumcombination of small carrier and drug, and do not provide the maximumeffect possible from the least necessary amount of additive material.The optimisation of the use of the additive material is important forseveral reasons. Firstly, it is clearly desirable to provide a drypowder formulation with the best possible powder properties in order toensure efficient, reliable and accurate dosing. Secondly, it is alsodesirable to minimise the amount of the additive material (or indeed ofany material) administered to the lung. This will reduce the risk ofadverse effects that may be caused by the material. Thirdly, it isdesirable to be able to deliver the maximum dose with optimum efficiencyfrom a minimum powder payload, especially for high dose drugs. Finally,the use of as little additive material as possible will also be moreeconomical. These features will also help to keep the device size small,maximise number of doses per device and reduce device complexity.

The present invention seeks to improve upon the powder formulationsprovided in the prior art, to ensure that their powder properties areoptimised and the powder preparation is simple and economical.

It is also an object of the present invention to permit an increasedpercentage of ultra-fine drug to be used in a formulation, optionallywith a fine carrier component, whilst still providing a powderformulation which exhibits improved flow, and improved aerosolisationdue to the individually tailored surface conditioning of the respectivedrug and carrier particles.

It has been found that the most advantageous powder system incorporatesone or more additives or force control agents on the surface of the boththe drug particles and the carrier particles, in order to maximise thepotential for flow and aerosolisation.

In the prior art, it is generally not suggested to attach the additiveto both the active particles and carrier or excipient particles toobtain the advantages outlined here.

The minimum amount of the additive or FCA necessary to improve powderproperties is preferably used, for toxicology and dosing reasons. Whatis more, the ideal incorporation of the additive is in the form of atleast an approximate single minimum layer of additive material as acoating around each powder component, that is around both the activeparticles and any carrier particles present. As the drug particles aregenerally smaller (i.e. less than 5 μm), they will have acorrespondingly higher surface area to volume ratio than the generallylarger (>5 μm) carrier particles.

According to a first aspect of the present invention, a method ofpreparing a powder formulation is provided, the method comprisingco-milling active particles with an additive material, separatelyco-milling carrier particles with an additive material, and thencombining the co-milled active and carrier particles.

The co-milling steps preferably produce composite particles of activeand additive material or carrier and additive material.

The powder formulations prepared according to the methods of the presentinvention exhibit excellent powder properties that may be tailored tothe active agent, the dispensing device to be used and/or various otherfactors. In particular, the co-milling of active and carrier particlesin separate steps allows different types of additive material anddifferent quantities of additive material to be milled with the activeand carrier particles. Consequently, the additive material can beselected to match its desired function, and the minimum amount ofadditive material can be used to match the relative surface area of theparticles to which it is being applied.

In one embodiment, the active particles and the carrier particles areboth co-milled with the same additive material or additive materials. Inan alternative embodiment, the active and carrier particles areco-milled with different additive materials.

In one embodiment of the invention, active particles of less than about5 μm diameter are co-milled with an appropriate amount of an additive orforce control agent, whilst carrier particles with a median diameter inthe range of about 3 μm to about 40 μm are separately co-milled with anappropriate amount of an additive.

Generally, the amount of additive co-milled with the carrier particleswill be less, by weight, than that co-milled with the active particles.Nevertheless, the amount of additive used is kept to a minimum whilstbeing sufficient to have the desired effect on the powder properties.The treated drug and carrier particles are then combined to provide aformulation with the desired features.

The additive material is preferably in the form of a coating on thesurfaces of the active and carrier particles. The coating may be adiscontinuous coating. In another embodiment, the additive material maybe in the form of particles adhering to the surfaces of the active andcarrier particles. Preferably, the additive material actually becomesfused to the surfaces of the active and carrier particles

It is advantageous for carrier particles to be used in the size rangehaving a median diameter of about 3 to about 40 μm, preferably about 5to about 30 μm, more preferably about 5 to about 20 μm, and mostpreferably about 5 to about 15 μm. Such particles, if untreated with anadditive are unable to provide suitable flow properties whenincorporated in a powder formulation comprising ultra-fine activeparticles. Indeed, previously, particles in these size ranges would nothave been regarded as suitable for use as carrier particles, and insteadwould have been added in small quantities as a fine component. Such finecomponents are known to increase the aerosolisation properties offormulations containing a drug and a larger carrier, typically withmedian diameter 40 μm to 100 μm or greater. However, the amount of thefine components that may be included in such formulations is limited,and formulations including more than about 10% fines tend to exhibitpoor properties unless special carrier particles are included, such asthe large fissured lactose carrier particles mentioned above.

Alternatively, compositions of micronised drug and micronised lactoseare known, but only where this blend has subsequently been successfullycompressed and granulated into pellets. This process is generally verydifficult to control and pellets are prone to destruction, resulting inpowders with poor flow properties.

However, following treatment with additive materials, substantialchanges in the powder characteristics of our fine carrier powders areseen. Powder density is increased, even doubled, for example from 0.3g/cc to over 0.5 g/cc. Other powder characteristics are changed, forexample, the angle of repose is reduced and contact angle increased.

Carrier particles having a median diameter of 3 to 40 μm areadvantageous as their relatively small size means that they have areduced tendency to segregate from the drug component, even when theyhave been treated with an additive, which will reduce cohesion. This isbecause the size differential between the carrier and drug is relativelysmall compared to that in conventional formulations which includeultra-fine active particles and much lager carrier particles. Thesurface area to volume ratio presented by the fine carrier particles iscorrespondingly greater than that of conventional large carrierparticles. This higher surface area, allows the carrier to besuccessfully associated with higher levels of drug than for conventionallarger carrier particles.

Carrier particles may be of any acceptable inert excipient material orcombination of materials. For example, carrier particles frequently usedin the prior art may be composed of one or more materials selected fromsugar alcohols, polyols and crystalline sugars. Other suitable carriersinclude inorganic salts such as sodium chloride and calcium carbonate,organic salts such as sodium lactate and other organic compounds such aspolysaccharides and oligosaccharides. Advantageously, the carrierparticles comprise a polyol. In particular, the carrier particles may beparticles of crystalline sugar, for example mannitol, dextrose orlactose. Preferably, the carrier particles are composed of lactose.

Advantageously, the additive material or FCA includes one or morecompounds selected from amino acids and derivatives thereof, andpeptides and derivatives thereof. Amino acids, peptides and derivativesof peptides are physiologically acceptable and give acceptable releaseof the active particles on inhalation.

It is particularly advantageous for the additive to comprise an aminoacid. The additive may comprise one or more of any of the followingamino acids: leucine, isoleucine, lysine, valine, methionine, andphenylalanine. The additive may be a salt or a derivative of an aminoacid, for example aspartame or acesulfame K. Preferably, the additiveconsists substantially of an amino acid, more preferably of leucine,advantageously L-leucine. The D-and DL-forms may also be used. Asindicated above, leucine has been found to give particularly efficientdispersal of the active particles on inhalation.

The additive may include one or more water soluble substances. Thishelps absorption of the additive by the body if it reaches the lowerlung. The additive may include dipolar ions, which may be zwitterions.It is also advantageous to include a spreading agent as an additive, toassist with the dispersal of the composition in the lungs. Suitablespreading agents include surfactants such as known lung surfactants(e.g. ALEC™) which comprise phospholipids, for example, mixtures of DPPC(dipalmitoyl phosphatidylcholine) and PG (phosphatidylglycerol). Othersuitable surfactants include, for example, dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoyl phosphatidylinositol(DPPI).

The additive may comprise a metal stearate, or a derivative thereof, forexample, sodium stearyl fumarate or sodium stearyl lactylate.Advantageously, it comprises a metal stearate, for example, zincstearate, magnesium stearate, calcium stearate, sodium stearate orlithium stearate. Preferably, the additive material comprises magnesiumstearate, for example vegetable magnesium stearate, or any form ofcommercially available metal stearate, which may be of vegetable oranimal origin and may also contain other fatty acid components such aspalmitates or oleates.

The additive may include or consist of one or more surface activematerials, in particular materials that are surface active in the solidstate, which may be water soluble or water dispersible, for examplelecithin, in particular soya lecithin, or substantially water insoluble,for example solid state fatty acids such as oleic acid, lauric acid,palmitic acid, stearic acid, erucic acid, behenic acid, or derivatives(such as esters and salts) thereof such as glyceryl behenate. Specificexamples of such materials are phosphatidylcholines,phosphatidylethanolamines, phosphatidylglycerols and other examples ofnatural and synthetic lung surfactants; lauric acid and its salts, forexample, sodium lauryl sulphate, magnesium lauryl sulphate;triglycerides such as Dynsan 118 and Cutina HR; and sugar esters ingeneral. Alternatively, the additive may be cholesterol.

Other possible additive materials include sodium benzoate, hydrogenatedoils which are solid at room temperature, talc, titanium dioxide,aluminium dioxide, silicon dioxide and starch. Also useful as additivesare film-forming agents, fatty acids and their derivatives, as well aslipids and lipid-like materials.

In one embodiment of the invention, the additive comprises an aminoacid, a derivative of an amino acid, a metal stearate or a phospholipid.Preferably, the additive comprises one or more of L-, D- or DL-forms ofleucine, isoleucine, lysine, valine, methionine, phenylalanine, orAerocine™, lecithin or magnesium stearate. In another embodiment, theadditive comprises leucine and preferably L-leucine.

In some embodiments, a plurality of different additive materials can beused.

The present invention can be carried out with any pharmaceuticallyactive agent. The terms “active particles” and “particles of activematerial” and the like are used interchangeably herein. The activeparticles comprise one or more pharmaceutically active agents. Thepreferred active agents include:

1) steroid drugs such as alcometasone, beclomethasone, beclomethasonedipropionate, betamethasone, budesonide, ciclesonide, clobetasol,deflazacort, diflucortolone, desoxymethasone, dexamethasone,fludrocortisone, flunisolide, fluocinolone, fluometholone, fluticasone,fluticasone proprionate, hydrocortisone, triamcinolone, nandrolonedecanoate, neomycin sulphate, rimexolone, methylprednisolone andprednisolone;

2) bronchodilators such as β2-agonists including salbutamol, formoterol,salmeterol, fenoterol, bambuterol, bitolterol, sibenadet,metaproterenol, epinephrine, isoproterenol, pirbuterol, procaterol,terbutaline and isoetharine antimuscarinics including ipratropium andtiotropium, and xanthines including aminophylline and theophylline;

3) nitrates such as isosorbide mononitrate, isosorbide dinitrate andglyceryl trinitrate;

4) antihistamines such as azelastine, chlorpheniramine, astemizole,cetirizine, cinnarizine, desloratadine, loratadine, hydroxyzine,diphenhydramine, fexofenadine, ketotifen, promethazine, trimeprazine andterfenadine;

5) anti-inflammatory agents such as piroxicam, nedocromil, benzydamine,diclofenac sodium, ketoprofen, ibuprofen, heparinoid, cromoglycate,fasafungine, iodoxamide and p38 MAP kinase inhibitors;

6) anticholinergic agents such as atropine, benzatropine, biperiden,cyclopentolate, oxybutinin, orphenadine, glycopyrronium, glycopyrrolate,procyclidine, propantheline, propiverine, tiotropium, trihexyphenidyl,tropicamide, trospium, ipratropium bromide and oxitroprium bromide;

7) leukotriene receptor antagonists such as montelukast and zafirlukast;

8) anti-allergics such as ketotifen;

9) anti-emetics such as bestahistine, dolasetron, nabilone,prochlorperazine, ondansetron, trifluoperazine, tropisetron,domperidone, hyoscine, cinnarizine, metoclopramide, cyclizine,dimenhydrinate and promethazine;

10) hormonal drugs (including hormone analogues) such as lanreotide,octreotide, insulin, pegvisomant, protirelin, thyroxine, salcotonin,somatropin, tetracosactide, vasopressin and desmopressin;

11) sympathomimetic drugs such as adrenaline, noradrenaline,dexamfetamine, dipirefin, dobutamine, dopexamine, phenylephrine,isoprenaline, dopamine, pseudoephedrine, tramazoline and xylometazoline;

12) opioids, preferably for pain management, such as buprenorphine,dextromoramide, dextropropoxypene, diamorphine, codeine,dextropropoxyphene, dihydrocodeine, hydromorphone, papaveretum,pholcodeine, loperamide, fentanyl, methadone, morphine, oxycodone,phenazocine, pethidine, tramadol and combinations thereof with ananti-emetic;

13) analgesics such as aspirin and other salicylates, paracetamol,clonidine, codine, coproxamol, ergotamine, gabapentin, pregabalin,sumatriptan, and non-steroidal anti-inflammatory drugs (NSAIDs)including celecoxib, etodolac, etoricoxib and meloxicam;

14) acetylcholinesterase inhibitors such as donepezil, galantamine andrivastigmine;

15) immunomodulators such as interferon (e.g. interferon beta-la andinterferon beta-1b) and glatiramer;

16) NMDA receptor antagonists such as mementine;

17) hypoglycaemics such as sulphonylureas including glibenclamide,gliclazide, glimepiride, glipizide and gliquidone, biguanides includingmetformin, thiazolidinediones including pioglitazone, rosiglitazone,nateglinide, repaglinide and acarbose;

18) narcotic agonists and opiate antidotes such as naloxone, andpentazocine;

19) phosphodiesterase inhibitors such as non-specific phosphodiesteraseinhibitors including theophylline, theobromine, IBMX, pentoxifylline andpapaverine; phosphodiesterase type 3 inhibitors including bipyridinessuch as milrinone, amrinone and olprinone; imidazolones such aspiroximone and enoximone; imidazolines such as imazodan and5-methyl-imazodan; imidazo-quinoxalines; and dihydropyridazinones suchas indolidan and LY181512(5-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-1,3-dihydro-indo1-2-one);dihydroquinolinone compounds such as cilostamide, cilostazol, andvesnarinone; phosphodiesterase type 4 inhibitors such as cilomilast,etazolate, rolipram, roflumilast and zardaverine, and includingquinazolinediones such as nitraquazone and nitraquazone analogs;xanthine derivatives such as denbufylline and arofylline;tetrahydropyrimidones such as atizoram; and oxime carbamates such asfilaminast; and phosphodiesterase type 5 inhibitors includingsildenafil, zaprinast, vardenafil, tadalafil, dipyridamole, and thecompounds described in WO 01/19802, particularly(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxy-benzylamino)-5-[N

(2-pyrimidinylmethyl)carbamoyl]pyrimidine, 2-(5,6,7,8-tetrahydro-1,7-naphthyridin

7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]-pyrimidine,and (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxy

benzylamino)-5[N-(1,3,5-trimethyl-4-pyrazolyl)carbamoyl]-pyrimidine);

20) antidepressants such as tricyclic and tetracyclic antidepressantsincluding amineptine, amitriptyline, amoxapine, butriptyline,cianopramine, clomipramine, dosulepin, doxepin, trimipramine,clomipramine, lofepramine, nortriptyline, tricyclic and tetracyclicamitryptiline, amoxapine, butriptyline, clomipramine, demexiptiline,desipramine, dibenzepin, dimetacrine, dothiepin, doxepin, imipramine,iprindole, levoprotiline, lofepramine, maprotiline, melitracen,metapramine, mianserin, mirtazapine, nortryptiline, opipramol,propizepine, protriptyline, quinupramine, setiptiline, tianeptine andtrimipramine; selective serotonin and noradrenaline reuptake inhibitors(SNRIs) including clovoxamine, duloxetine, milnacipran and venlafaxine;selective serotonin reuptake inhibitors (SSRIs) including citalopram,escitalopram, femoxetine, fluoxetine, fluvoxamine, ifoxetine,milnacipran, nomifensine, oxaprotiline, paroxetine, sertraline,sibutramine, venlafaxine, viqualine and zimeldine; selectivenoradrenaline reuptake inhibitors (NARIS) including demexiptiline,desipramine, oxaprotiline and reboxetine; noradrenaline and selectiveserotonin reuptake inhibitors (NASSAs) including mirtazapine; monoamineoxidase inhibitors (MAOIs) including amiflamine, brofaromine,clorgyline, α-ethyltryptamine, etoperidone, iproclozide, iproniazid,isocarboxazid, mebanazine, medifoxamine, moclobemide, nialamide,pargyline, phenelzine, pheniprazine, pirlindole, procarbazine,rasagiline, safrazine, selegiline, toloxatone and tranylcypromine;muscarinic antagonists including benactyzine and dibenzepin; azaspironesincluding buspirone, gepirone, ipsapirone, tandospirone and tiaspirone;and other antidepressants including amesergide, amineptine, benactyzine,bupropion, carbamazepine, fezolamine, flupentixol, levoprotiline,maprotiline, medifoxamine, methylphenidate, minaprine, nefazodone,nomifensine, oxaflozane, oxitriptan, rolipram, sibutramine,teniloxazine, tianeptine, tofenacin, trazadone, tryptophan, viloxazine,and lithium salts;

21) serotonin agonists such as 2-methyl serotonin, buspirone,ipsaperone, tiaspirone, gepirone, lysergic acid diethylamide, ergotalkaloids, 8-hydroxy-(2-N,N

dipropylamino)-tetraline,1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane, cisapride, sumatriptan,m-chlorophenylpiperazine, trazodone, zacopride and mezacopride;

22) serotonin antagonists including ondansetron, granisetron,metoclopramide, tropisetron, dolasetron, trimethobenzamide,methysergide, risperidone, ketanserin, ritanserin, clozapine,amitryptiline,R(+)-α-(2,3-dimethoxyphenyl)-1[2-(4-fluorophenyl)ethyl]-4-piperidine-methanol,azatadine, cyproheptadine, fenclonine, dexfenfluramine, fenfluramine,chlorpromazine and mianserin;

23) adrenergic agonists including methoxamine, methpentermine,metaraminol, mitodrine, clonidine, apraclonidine, guanfacine, guanabenz,methyldopa, amphetamine, methamphetamine, epinephrine, norepinephrine,ethylnorepinephrine, phenylephrine, ephedrine, pseudo-ephedrine,methylphenidate, pemoline, naphazoline, tetrahydrozoline, oxymetazoline,xylometazoline, phenylpropanolamine, phenylethylamine, dopamine,dobutamine, colterol, isoproterenol, isotharine, metaproterenol,terbutaline, metaraminol, tyramine, hydroxyamphetamine, ritodrine,prenalterol, albuterol, isoetharine, pirbuterol, bitolterol, fenoterol,formoterol, procaterol, salmeterol, mephenterine and propylhexedrine;

24) adrenergic antagonists such as phenoxybenzamine, phentolamine,tolazoline, prazosin, terazosin, doxazosin, trimazosin, yohimbine, ergotalkaloids, labetalol, ketanserin, urapidil, alfuzosin, bunazosin,tamsulosin, chlorpromazine, haloperidol, phenothiazines, butyrophenones,propranolol, nadolol, timolol, pindolol, metoprolol, atenolol, esmolol,acebutolol, bopindolol, carteolol, oxprenolol, penbutolol, carvedilol,medroxalol, naftopidil, bucindolol, levobunolol, metipranolol,bisoprolol, nebivolol, betaxolol, carteolol, celiprolol, sotalol,propafenone and indoramin;

25) adrenergic neurone blockers such as bethanidine, debrisoquine,guabenxan, guanadrel, guanazodine, guanethidine, guanoclor and guanoxan;

26) benzodiazepines such as alprazolam, bromazepam, brotizolam,chlordiazepoxide, clobazam, clonazepam, clorazepate, demoxepam,diazepam, estazolam, flunitrazepam, flurazepam, halazepam, ketazolam,loprazolam, lorazepam, lormetazepam, medazepam, midazolam, nitrazepam,nordazepam, oxazepam, prazepam, quazepam, temazepam and triazolam;

27) mucolytic agents such as N-acetylcysteine, recombinant human DNase,amiloride, dextrans, heparin, desulphated heparin and low molecularweight heparin;

28) antibiotic and antibacterial agents such as metronidazole,sulphadiazine, triclosan, neomycin, amoxicillin, amphotericin,clindamycin, aclarubicin, dactinomycin, nystatin, mupirocin andchlorhexidine;

29) anti-fungal drugs such as caspofungin, voriconazole, polyeneantibiotics including amphotericin, and nystatin, imidazoles andtriazoles including clotrimazole, econazole nitrate, fluconazole,ketoconazole, itraconazole, terbinafine and miconazole;

30) antivirals such as oseltamivir, zanamivir, amantadine, inosinepranobex and palivizumab, DNA polymerase inhibitors including aciclovir,adefovir and valaciclovir, nucleoside analogues including famiciclovir,penciclovir and idoxuridine and interferons;

31) vaccines;

32) immunoglobulins;

33) local anaesthetics such as amethocaine, bupivacaine, hydrocortisone,methylprednisolone, prilocaine, proxymetacaine, ropivacaine,tyrothricin, benzocaine and lignocaine;

34) anticonvulsants such as sodium valproate, carbamazepine,oxcarbazepine, phenytoin, fosphenytoin, diazepam, lorazepam, clonazepam,clobazam, primidone, lamotrigine, levetiracetam, topiramate, gabapentin,pregabalin, vigabatrin, tiagabine, acetazolamide, ethosuximide andpiracetam;

35) angiotensin converting enzyme inhibitors such as captopril,cilazapril, enalapril, fosinopril, imidapril hydrochloride, lisinopril,moexipril hydrochloride, perindopril, quinapril, ramipril andtrandolapril;

36) angiotension II receptor blockers, such as candesartan, cilexetil,eprosartan, irbesartan, losartan, olmesartan medoxomil, telmisartan andvalsartan;

37) calcium channel blockers such as amlodipine, bepridil, diltiazem,felodipine, flunarizine, isradipine, lacidipine, lercanidipine,nicardipine, nifedipine, nimodipine and verapamil;

38) alpha-blockers such as indoramin, doxazosin, prazosin, terazosin andmoxisylate;

39) antiarrhythmics such as adenosine, propafenone, amidodarone,flecainide acetate, quinidine, lidocaine hydrochloride, mexiletine,procainamide and disopyramide;

40) anti-clotting agents such as aspirin, heparin and low molecularweight heparin, epoprostenol, dipyridamole, clopidogrel, alteplase,reteplase, streptokinase, tenecteplase, certoparin, heparin calcium,enoxaparin, dalteparin, danaparoid, fondaparin, lepirudin, bivalirudin,abciximab, eptifibatide, tirofiban, tinzaparin, warfarin, lepirudin,phenindione and acenocoumarol;

41) potassium channel modulators such as nicorandil, cromakalim,diazoxide, glibenclamide, levcromakalim, minoxidil and pinacidil;

42) cholesterol-lowering drugs such as colestipol, colestyramine,bezafibrate, fenofibrate, gemfibrozil, ciprofibrate, rosuvastatin,simvastatin, fluvastatin, atorvastatin, pravastatin, ezetimibe,ispaghula, nictotinic acid, acipimox and omega-3 triglycerides;

43) diuretics such as bumetanide, furosemide, torasemide,spironolactone, amiloride, bendroflumethiazide, chlortalidone,metolazone, indapamide and cyclopenthiazide;

44) smoking cessation drugs such as nicotine and bupropion;

45) bisphosphonates such as alendronate sodium, sodium clodronate,etidronate disodium, ibandronic acid, pamidronate disodium, isedronatesodium, tiludronic acid and zoledronic acid;

46) dopamine agonists such as amantadine, bromocriptine, pergolide,cabergoline, lisuride, ropinerole, pramipexole and apomorphine;

47) nucleic-acid medicines such as oligonucleotides, decoy nucleotides,antisense nucleotides and other gene-based medicine molecules;

48) antipsychotics such as: dopamine antagonists includingchlorpromazine, prochlorperazine, fluphenazine, trifluoperazine andthioridazine; phenothiazines including aliphatic compounds, piperidinesand piperazines; thioxanthenes, butyrophenones and substitutedbenzamides; atypical antipsychotics including clozapine, risperidone,olanzapine, quetiapine, ziprasidone, zotepine, amisulpride andaripiprazole; and

49) pharmaceutically acceptable salts or derivatives of any of theforegoing.

In preferred embodiments of the present invention, the active agent isheparin (fractionated and unfractionated), apomorphine, clobazam,clomipramine or glycopyrrolate.

In addition, the active agents used in the present invention may besmall molecules, proteins, carbohydrates or mixtures thereof.

The term co-milling is used herein to refer to a range of methods,including co-micronising methods, some examples of which are outlinedbelow. In the prior art, co-milling or co-micronising active agents orexcipients with additive materials has been suggested.

It is stated that milling can be used to substantially decrease the sizeof particles of active agent. However, if the particles of active agentare already fine, for example have a MMAD of less than 20 μm prior tothe milling step, the size of those particles may not be significantlyreduced where the milling of these active particles takes place in thepresence of an additive material. Rather, milling of fine activeparticles with additive particles using the methods described in theprior art (for example, in the earlier patent application published asWO 02/43701) will result in the additive material becoming deformed andbeing smeared over or fused to the surfaces of the active particles. Theresultant composite active particles have been found to be less cohesivefollowing the milling treatment.

The prior art mentions two types of processes in the context ofco-milling or co-micronising active and additive particles. First, thereis the compressive type process, such as Mechanofusion and the Cyclomixand related methods such as the Hybridiser or the Nobilta. As the namesuggests, Mechanofusion is a dry coating process designed tomechanically fuse a first material onto a second material. The firstmaterial is generally smaller and/or softer than the second. Theprinciples behind the Mechanofusion and Cyclomix processes are distinctfrom those of alternative milling techniques in that they have aparticular interaction between an inner element and a vessel wall, andin that they are based on providing energy by a controlled andsubstantial compressive force.

The fine active particles and the additive particles are fed into theMechanofusion driven vessel (such as a Mechanofusion system (HosokawaMicron Ltd)), where they are subject to a centrifugal force whichpresses them against the vessel inner wall. The inner wall and a curvedinner element together form a gap or nip in which the particles arepressed together. The powder is compressed between the fixed clearanceof the drum wall and a curved inner element with high relative speedbetween drum and element. As a result, the particles experience veryhigh shear forces and very strong compressive stresses as they aretrapped between the inner drum wall and the inner element (which has agreater curvature than the inner drum wall). The particles are pressedagainst each other with enough energy to locally heat and soften, break,distort, flatten and wrap the additive particles around the activeparticles to form coatings. The energy is generally sufficient to breakup agglomerates and some degree of size reduction of both components mayoccur. Whilst the coating may not be complete, the deagglomeration ofthe particles during the process ensures that the coating may besubstantially complete, covering the majority of the surfaces of theparticles.

These Mechanofusion and Cyclomix processes apply a high enough degree offorce to separate the individual particles of active material and tobreak up tightly bound agglomerates of the active particles such thateffective mixing and effective application of the additive material tothe surfaces of those particles is achieved.

An especially desirable aspect of the described co-milling processes isthat the additive material becomes deformed during the milling and maybe smeared over or fused to the surfaces of the active particles.However, in practice, this compression process produces little or nosize reduction of the drug particles, especially where they are alreadyin a micronised form (i.e. <10 μm). The only physical change which maybe observed is a plastic deformation of the particles to a roundershape.

However the most preferred milling techniques include those described inR. Pfeffer et al. “Synthesis of engineered particulates with tailoredproperties using dg particle coating”, Powder Technology 117 (2001)40-67. These include processes using the MechanoFusion® machine, theHybidizer® machine, the Theta Composer®, magnetically assisted impactionprocesses and rotating fluidised bed coaters. Cyclomix methods may alsobe used.

Preferably, the technique employed to apply the required mechanicalenergy involves the compression of a mixture of particles of thedispersing agent and particles of the pharmaceutically active agent in anip formed between two portions of a milling machine, as is the case inthe MechanoFusion® and Cyclomix devices. Some preferred milling methodswill now be described in greater detail:

MechanoFusion®:

As the name suggests, this dry coating process is designed tomechanically fuse a first material onto a second material. The firstmaterial is generally smaller and/or softer than the second. TheMechanoFusion and Cyclomix working principles are distinct fromalternative milling techniques in having a particular interactionbetween inner element and vessel wall, and are based on providing energyby a controlled and substantial compressive force.

The fine active particles and the particles of dispersing agent are fedinto the MechanoFusion driven vessel, where they are subject to acentrifugal force and are pressed against the vessel inner wall. Thepowder is compressed between the fixed clearance of the drum wall and acurved inner element with high relative speed between drum and element.The inner wall and the curved element together form a gap or nip inwhich the particles are pressed together. As a result the particlesexperience very high shear forces and very strong compressive stressesas they are trapped between the inner drum wall and the inner element(which has a greater curvature than the inner drum wall). The particlesviolently collide against each other with enough energy to locally heatand soften, break, distort, flatten and wrap the particles of dispersingagent around the core particle to form a coating. The energy isgenerally sufficient to break up agglomerates and some degree of sizereduction of both components may occur. Embedding and fusion of additiveparticles of dispersing agent onto the active particles may occur, andmay be facilitated by the relative differences in hardness (andoptionally size) of the two components. Either the outer vessel or theinner element may rotate to provide the relative movement. The gapbetween these surfaces is relatively small, and is typically less than10 mm and is preferably less than 5 mm, more preferably less than 3 mm.This gap is fixed, and consequently leads to a better control of thecompressive energy than is provided in some other forms of mill such asball and media mills. Also, in general, no impaction of milling mediasurfaces is present so that wear and consequently contamination areminimised. The speed of rotation may be in the range of 200 to 10,000rpm. A scraper may also be present to break up any caked materialbuilding up on the vessel surface. This is particularly advantageouswhen using fine cohesive starting materials. The local temperature maybe controlled by use of a heating/cooling hacked built into the drumvessel walls. The powder may be re-circulated through the vessel.

Cyclomix Method (Hosokawa Microm):

The cyclomix comprises a stationary conical vessel with a fast rotatingshaft with paddles which move close to the wall. Due to the highrotational speed of the paddles, the powder is propelled towards thewall, and as a result the mixture experiences very high shear forces andcompressive stresses between wall and paddle. Such effects are similarto those in MechanoFusion as described above and may be sufficient tolocally heat and soften, to break, distort, flatten and wrap theparticles of dispersing agent around the active particles to form acoating. The energy is sufficient to break up agglomerates and somedegree of size reduction of both components may also occur depending onthe conditions and upon the size and nature of the particles.

Hybridiser® Method:

This is a dry process which can be described as a product embedding orfilming of one powder onto another. The fine active particles and fineor ultra fine particles of dispersing agent are fed into a conventionalhigh shear mixer pre-mix system to form an ordered mixture. This powderis then fed into the Hybridiser. The powder is subjected to ultra-highspeed impact, compression and shear as it is impacted by blades on ahigh speed rotor inside a stator vessel, and is re-circulated within thevessel. The active and additive particles collide with each other.Typical speeds of rotation are in the range of 5,000 to 20,000 rpm. Therelatively soft fine particles of dispersing agent experience sufficientimpact force to soften, break, distort, flatten and wrap around theactive particle to form a coating. There may also be some degree ofembedding into the surface of the active particles.

The second of the types of processes mentioned in the prior art is theimpact milling processes. Such impact milling is involved, for example,in ball milling, jet milling and the use of a homogeniser.

Ball milling is a milling method used in many of the prior artco-milling processes. Centrifugal and planetary ball milling areespecially preferred methods.

Jet mills are capable of reducing solids to particle sizes in thelow-micron to submicron range. The grinding energy is created by gasstreams from horizontal grinding air nozzles. Particles in the fluidisedbed created by the gas streams are accelerated towards the centre of themill, colliding with slower moving particles. The gas streams and theparticles carried in them create a violent turbulence and, as theparticles collide with one another, they are pulverized.

High pressure homogenisers involve a fluid containing the particlesbeing forced through a valve at high pressure, producing conditions ofhigh shear and turbulence. Suitable homogenisers include EmulsiFlex highpressure homogenisers which are capable of pressures up to 4000 bar,Niro Soavi high pressure homogenisers (capable of pressures up to 2000bar) and Micro fluidics Microfluidisers (maximum pressure 2750 bar).

Milling may, alternatively, involve a high energy media mill or anagitator bead mill, for example, the Netzsch high energy media mill, orthe DYNO-mill (Willy A. Bachofen AG, Switzerland).

All of these processes create high-energy impacts between media andparticles or between particles. In practice, while these processes aregood at making very small particles, it has been found that the ballmill, jet mill and the homogenizer were not as effective in producingdispersion improvements in resultant drug powders as the compressivetype processes. It is believed that the impact processes discussed aboveare not as effective in producing a coating of additive material on eachparticle as the compressive type processes.

For the purposes of this invention, all forms of co-milling andco-micronisation are encompassed, including methods that are similar orrelated to all of those methods described above. For example, methodssimilar to Mechanofusion are encompassed, such as those utilizing one ormore very high-speed rotors (i.e. 2000 to 50000 rpm) with blades orother elements sweeping the internal surfaces of the vessels with smallgaps between wall and blade (i.e. 0.1 mm to 20 mm). Conventional methodscomprising co-milling active material with additive materials (asdescribed in WO 02/43701) are also encompassed. These methods result incomposite active particles comprising ultra-fine active particles withan amount of the additive material on their surfaces.

Thus, the milling methods used in the present invention are simple andcheap compared to the complex previous attempts to engineer particles,providing practical as well as cost benefits. A further benefitassociated with the present invention is that the powder processingsteps do not have to involve organic solvents. Such organic solvents arecommon to many of the known approaches to powder processing and areknown to be undesirable for a variety of reasons.

In the past, jet milling has been considered less attractive forco-milling active and additive particles in the preparation of powderformulations to be dispensed using passive devices, with compressiveprocesses like or related to Mechanofusion and Cyclomixing beingpreferred. The collisions between the particles in a jet mill aresomewhat uncontrolled and those skilled in the art, therefore,considered it unlikely that this technique would be able to provide thedesired deposition of a coating of additive material on the surface ofthe active particles.

Moreover, it was believed that, unlike the situation with compressivetype processes such as Mechanofusion and Cyclomixing, segregation of thepowder constituents occurred in jet mills, such that the finerparticles, that were believed to be the most effective, could escapefrom the process. In contrast, it could be clearly envisaged howtechniques such as Mechanofusion would result in the desired coating.

However, more recently, jet milling has been shown to be an attractiveprocess for co-milling active and additive particles, especially forpreparing powder formulations that are to be used in active devices (seethe disclosure in the earlier patent application published as WO2004/001628).

It should also be noted that it was also previously believed that thecompressive or impact milling processes must be carried out in a closedsystem, in order to prevent segregation of the different particles. Thishas also been found to be untrue and the co-milling processes used inthe present invention do not need to be carried out in a closed system.In an open system, the co-jet milling has surprisingly been found not toresult in the loss of the small particles, even when using leucine asthe additive material. Leucine was previously considered to presentsomething of a problem when co-jet milled.

Further, co-jet milling at lower pressures can produce powders whichperform well in passive devices whilst powders milled at higherpressures may perform better in active devices, such as Aspirair™.

The co-milling processes can be specifically selected for the active andcarrier particles. For example, the active particles may be co-jetmilled or homogenized with the additive, whilst the carrier particlesmay be mechanofused with the additive.

The co-milling processes according to the present invention may becarried out in two or more stages, to provide beneficial effects.Various combinations of types of co-milling and/or additive material maybe used, in order to obtain advantages. Within each step, multiplecombinations of co-milling and other processing steps may be used.

For example, milling at different pressures and/or different types ofmilling or blending processes may be combined. The use of multiple stepsallows one to tailor the properties of the milled particles to suit aparticular inhaler device, a particular drug and/or to target particularparts of the lung.

In one embodiment of the present invention, the milling process is atwo-step process comprising first jet milling the drug on its own atsuitable grinding pressure to obtain the required particle sizes. Next,the milled drug is co-milled with an additive material. Preferably, thissecond step is carried out at a lower grinding pressure, so that theeffect achieved is the coating of the small active particles with theadditive material. This two-step process may produce better results thansimply co-milling the active material and additive material at a highgrinding pressure.

The same type of two-step milling process can be carried out with thecarrier particles, although these particles, as a rule, do not have tobe milled to such small particle sizes.

In another embodiment of the present invention, the composite particles,which may optionally have been produced using the two-step co-millingprocess discussed above, subsequently undergo Mechanofusion. This finalMechanofusion step may “polish” the composite particles, further rubbingthe additive material into the particles. This provides beneficialproperties afforded by Mechanofusion, in combination with the very smallparticles sizes made possible by the co jet milling. Such an additionalMechanofusion step is particularly attractive for composite activeparticles, especially where they are very small.

The reduction in particle size may be increased by carrying out theco-jet milling at lower temperatures. Whilst the co jet milling processmay be carried out at temperatures between −20° C. and 40° C., theparticles will tend to be more brittle at lower temperatures and theytherefore fracture more readily so that the milled particles tend to beeven smaller. Therefore, in another embodiment of the present invention,the jet milling is carried out at temperatures below room temperature,preferably at a temperature below 10° C., more preferably at atemperature below 0° C.

The benefits of the methods according to the present invention areillustrated by the experimental data set out below.

COMPARATIVE EXAMPLES Example 1 Mechanofused Budesonide with MagnesiumStearate

This example studied magnesium stearate processed with budesonide. Theblends were prepared by Mechanofusion using the Hosokawa AMS-MINI, withblending being carried out for 60 minutes at approximately 4000 rpm.

The magnesium stearate used was a standard grade supplied by AvocadoResearch Chemicals Ltd. The drug used was micronised budesonide. Thepowder properties were tested using the Miat Monohaler.

Blends of budesonide and magnesium stearate were prepared at differentweight percentages of magnesium stearate. Blends of 5% w/w and 10% w/w,were prepared and then tested. MSLIs and TSIs were carried out on theblends. The results, which are summarised below, indicate a highaerosolisation efficiency. However, this powder had poor flowproperties, and was not easily handled, giving high device retention.

FPF FPD ED Formulation (ED) (mg) (mg) Method Budesonide:magnesium 73%1.32 1.84 MSLI stearate (5% w/w) Budesonide:magnesium 80% 1.30 1.63 TSIstearate (10% w/w)

Example 2 Mechanofused Budesonide with Fine Lactose and MagnesiumStearate

A further study was conducted to look at the Mechanofusion of a drugwith both a force control agent and fine lactose particles. The additiveor force control agent used was magnesium stearate (Avocado) and thefine lactose was Sorbolac 400 (Meggle). The drug used was micronisedbudesonide.

The blends were prepared by Mechanofusion of all three componentstogether using the Hosokawa AMS-MINI, blending was carried out for 60minutes at approximately 4000 rpm.

Formulations were prepared using the following concentrations ofbudesonide, magnesium stearate and Sorbolac 400:

-   -   5% w/w budesonide, 6% w/w magnesium stearate, 89% w/w Sorbolac        400; and    -   20% w/w budesonide, 6% w/w magnesium stearate, 74% w/w Sorbolac        400.

TSIs and MSLIs were performed on the blends. The results, which aresummarised below, indicate that, as the amount of budesonide in theblends increased, the FPF results increased. Device and capsuleretention were notably low in these dispersion tests (<5%), however arelatively large level of magnesium stearate was used and this wasapplied over the entire composition.

FPF(ED) FPF(ED) Formulation (TSI) (MSLI)  5:6:89 66.0% 70.1% 20:6:7475.8% —

As an extension to this work, different blending methods of budesonide,magnesium stearate and Sorbolac 400 were investigated further. Twoformulations were prepared in the Glen Creston Grindomix. This mixer isa conventional food-processor style bladed mixer, with 2 parallelblades.

The first of these formulations was a 5% w/w budesonide, 6% w/wmagnesium stearate, 89% w/w Sorbolac 400 blend prepared by mixing allcomponents together at 2000 rpm for 20 minutes. The formulation wastested by TSI and the results, when compared to those for themechanofused blends, showed the Grindomix blend to give lower FPFresults (see table below).

The second formulation was a blend of 90% w/w of mechanofused magnesiumstearate:Sorbolac 400 (5:95) pre-blend and 10% w/w budesonide blended inthe Grindomix for 20 minutes. The formulation was tested by TSI andMSLI.

It was also observed that this formulation had notably good flowproperties for a material comprising such fine particles. This isbelieved to be associated with the Mechanofusion process.

FPF (ED) FPF Formulation (TSI) (MSLI) Grindomix 5:6:89% 57.7 — Grindomix10% budesonide 65.9 69.1 (Mechanofused pre-blend)

Example 3 Mechanofused Salbutamol with Fine Lactose and MagnesiumStearate

A further study was conducted to look at the Mechanofusion of analternative drug with both a force control agent and fine lactoseparticles. The additive or force control agent used was magnesiumstearate and the fine lactose was Sorbolac 400 (Meggle). The drug usedwas micronised salbutamol sulphate. The blends were prepared byMechanofusion using the Hosokawa AMS-MINI, blending for 10 minutes atapproximately 4000 rpm.

Formulations prepared were:

-   -   20% w/w salbutamol, 5% w/w magnesium stearate, 75% w/w Sorbolac        400; and    -   20% w/w salbutamol, 2% w/w magnesium stearate, 78% w/w Sorbolac        400.

NGIs were performed on the blends and the results are set out below.Device and capsule retention were again low in these dispersion tests(<10%).

Formulation FPF (ED) FPF (ED) 20:5:75 80% 74% 20:2:78 78% 70%

Example 4 Preparation of Mechanofused Formulation for Use in a PassiveDevice

20 g of a mix comprising 20% micronised clomipramine, 78% Sorbolac 400(fine lactose) and 2% magnesium stearate were weighed into the HosokawaAMS-MINI Mechanofusion system via a funnel attached to the largest portin the lid with the equipment running at 3.5%. The port was sealed andthe cooling water switched on. The equipment was run at 20% for 5minutes followed by 80% for 10 minutes. The equipment was switched off,dismantled and the resulting formulation recovered mechanically.

20 mg of the collected powder formulation was filled into size 3capsules and fired from a Miat Monohaler into an NGI. The FPF measuredwas good, being greater than 70%.

The data above suggest that magnesium stearate content in the region5-20% yielded the greatest dispersibility. Above these levels,experience suggests significant sticking inside the device could occur,and the quantities used became unnecessary for further performanceimprovement.

Fine particle fraction values were consistently obtained in the range 50to 60%, and doubled in comparison with controls containing no magnesiumstearate.

EXAMPLES OF THE INVENTION Example 5 Mechanofused Apomorphine andMechanofused Fine Lactose

Firstly, 15 g of micronised apomorphine and 0.75 g leucine are weighedinto the Hosokawa AMS-MINI Mechanofusion system via a funnel attached tothe largest port in the lid with the equipment running at 3.5%. The portis sealed and the cooling water switched on. The equipment is run at 20%for 5 minutes followed by 80% for 10 minutes. The equipment is thenswitched off, dismantled and the resulting formulation recoveredmechanically.

Next, 19 g of Sorbolac 400 lactose and 1 g leucine are weighed into theHosokawa AMS-MINI Mechanofusion system via a funnel attached to thelargest port in the lid with the equipment running at 3.5%. The port issealed and the cooling water switched on. The equipment is run at 20%for 5 minutes followed by 80% for 10 minutes. The equipment is switchedoff, dismantled and the resulting formulation recovered mechanically.

4.2 g of the apomorphine-based material and 15.8 g of the Sorbolac-basedmaterial are combined in a high shear mixer for 5 minutes, and theresulting powder is then passed through a 300 micron sieve to form thefinal formulation. 2 mg of the powder formulation are filled intoblisters and fired from an Aspirair device into an NGI. An FPF of over50% was obtained with MMAD 1.5 microns, illustrating this system gave avery good dispersion. The device retention was also very low, withonly—1% left in the device and 7% in the blister.

Example 6 Mechanofused Clomipramine and Mechanofused Fine Lactose

Firstly, 20 g of a mix comprising 95% micronised clomipramine and 5%magnesium stearate are weighed into the Hosokawa AMS-MINI Mechanofusionsystem via a funnel attached to the largest port in the lid with theequipment running at 3.5%. The port is sealed and the cooling waterswitched on. The equipment is run at 20% for 5 minutes followed by 80%for 10 minutes. The equipment is then switched off, dismantled and theresulting formulation recovered mechanically.

Next, 20 g of a mix comprising 99% Sorbolac 400 lactose and 1% magnesiumstearate are weighed into the Hosokawa AMS-MINI Mechanofusion system viaa funnel attached to the largest port in the lid with the equipmentrunning at 3.5%. The port is sealed and the cooling water switched on.The equipment is run at 20% for 5 minutes followed by 80% for 10minutes. The equipment is switched off, dismantled and the resultingformulation recovered mechanically.

4 g of the clomipramine-based material and 16 g of the Sorbolac-basedmaterial are combined in a high shear mixer for 10 minutes, to form thefinal formulation. 20 mg of the powder formulation are filled into size3 capsules and fired from a Miat Monohaler into an NGI.

Example 7 Mechanofused Theophylline and Mechanofused Fine Lactose

Firstly, 20 g of a mix comprising 95% micronised theophylline and 5%magnesium stearate are weighed into the Hosokawa AMS-MINI Mechanofusionsystem via a funnel attached to the largest port in the lid with theequipment running at 3.5%. The port is sealed and the cooling waterswitched on. The equipment is run at 20% for 5 minutes followed by 80%for 10 minutes. The equipment is then switched off, dismantled and theresulting formulation recovered mechanically.

Next, 20 g of a mix comprising 99% Sorbolac 400 lactose and 1% magnesiumstearate are weighed into the Hosokawa AMS-MINI Mechanofusion system viaa funnel attached to the largest port in the lid with the equipmentrunning at 3.5%. The port is sealed and the cooling water switched on.The equipment is run at 20% for 5 minutes followed by 80% for 10minutes. The equipment is switched off, dismantled and the resultingformulation recovered mechanically.

4 g of the theophylline -based material and 16 g of the Sorbolac-basedmaterial are combined in a high shear mixer for 10 minutes, to form thefinal formulation. 20 mg of the powder formulation are filled into size3 capsules and fired from a Miat Monohaler into an NGI.

The active agent used in this example, theophylline, may be replaced byother phosphodiesterase inhibitors, including phosphodiesterase type 3,4 or 5 inhibitors, as well as other non-specific ones.

Example 8 Jet Milled Clomipramine and Mechanofused Fine Lactose

20 g of a mix comprising 95% micronised clomipramine and 5% magnesiumstearate are co-jet milled in a Hosokawa AS50 jet mill.

20 g of a mix comprising 99% Sorbolac 400 (fine lactose) and 1%magnesium stearate are weighed into the Hosokawa AMS-MINI Mechanofusionsystem via a funnel attached to the largest port in the lid with theequipment running at 3.5%. The port is sealed and the cooling waterswitched on. The equipment is run at 20% for 5 minutes followed by 80%for 10 minutes. The equipment is switched off, dismantled and theresulting formulation recovered mechanically.

4 g of the clomipramine-based material and 16 g of the Sorbolac-basedmaterial are combined in a high shear mixer for 10 minutes, to form thefinal formulation. 20 mg of the powder formulation are filled into size3 capsules and fired from a Miat Monohaler into an NGI.

A number of micronised drugs were co-jet milled with magnesium stearatefor the purposes of replacing the clomipramine in this example. Thesemicronised drugs included budesonide, formoterol, salbutamol,glycopyrrolate, heparin, insulin and clobazam. Further compounds areconsidered suitable, including the classes of active agents and thespecific examples listed above.

Example 9 Jet Milled Bronchodilator and Mechanofused Fine Lactose

20 g of a mix comprising 95% micronised bronchodilator drug and 5%magnesium stearate are co jet milled in a Hosokawa AS50 jet mill.

20 g of a mix comprising 99% Sorbolac 400 lactose and 1% magnesiumstearate are weighed into the Hosokawa AMS-MINI Mechanofusion system viaa funnel attached to the largest port in the lid with the equipmentrunning at 3.5%. The port is sealed and the cooling water switched on.The equipment is run at 20% for 5 minutes followed by 80% for 10minutes. The equipment is switched off, dismantled and the resultingformulation recovered mechanically.

4 g of the drug based material and 16 g of the Sorbolac based materialare combined in a high shear mixer for 10 minutes, to form the finalformulation.

20 mg of the powder formulation is filled into size 3 capsules and firedfrom a Miat Monohaler into an NGI.

The results of these experiments are expected to show that the powderformulations prepared using the method according to the presentinvention exhibit further improved properties such as FPD, FPF, as wellas good flow and reduced device retention and throat deposition.

In accordance with the present invention, the % w/w of additive materialwill typically vary. Firstly, when the additive material is added to thedrug, the amount used is preferably in the range of 0.1% to 50%, morepreferably 1% to 20%, more preferably 2% to 10%, and most preferably 3to 8%. Secondly, when the additive material is added to the carrierparticles, the amount used is preferably in the range of 0.01% to 30%,more preferably of 0.1% to 10%, preferably 0.2% to 5%, and mostpreferably 0.5% to 2%. The amount of additive material preferably usedin connection with the carrier particles will be heavily dependant uponthe size and hence surface area of these particles.

Example 10 Lactose Study

A study was conducted to characterize the changes in the properties offine carrier particles, and of ultra-fine drug particles, when they areco-milled with an additive material.

Micronised ultra-fine lactose was selected as a model for a drug, as itis readily available in a micronised form and it carries a reducedhazard compared to handling pharmaceutically active substances.Ultra-fine lactose is also regarded as a particularly cohesive material,hence improving its dispersibility represents a severe challenge.

Meggle Sorbolac 400 and Meggle Extra Fine were selected as the finecarrier grades, as these are readily available. However other lactosegrades can be used, such as those produced by DMV, Borculo, Foremost andother suppliers, or a grade custom-made for the purpose, as long as itconforms to the size range indicated.

The literature reveals various possible types of tests, includingmeasuring powder flow, powder cohesion, powder shear and powderdustiness.

In the first instance, several basic powder characteristics were tested.These were porosity and surface area using the Coulter SA 3100 BETsystem, and particle size, which was measured using a Mastersizer 2000,manufactured by Malvern Instruments, Ltd. (Malvern, UK). This wasfollowed by examining several standard powder properties using theHosokawa Powder Tester.

Porosity

The powder porosity was measured using the Coulter SA 3100 BET system,with the following results.

Total pore volume Sample (ml/g) Sorbolac 0.0027 Mechanofused Sorbolac(60 mins) 0.0044 Mechanofused Sorbolac and magnesium 0.0056 stearate(98:2) (60 mins) Mechanofused Sorbolac and magnesium 0.0052 stearate(95:5) (60 mins)

The microporosity of the lactose particles is also shown in the graph ofFIG. 1. Whilst the total pore volume does increase significantly uponprocessing, insufficient differences are seen in the different poresizes to use porosity testing as a measure of the process. Therefore,Malvern particle sizing of a wet powder dispersion was also conducted.The results are summarised below.

Surface Malvern Sample Area (m²/g) d₅₀ (gm) Sorbolac 1.023 8.760Magnesium Stearate 13.404 9.145 Mechanofused Sorbolac (60 mins) 1.1897.525 Mechanofused Sorbolac and magnesium 1.562 8.191 stearate (98:2) (0mins) Mechanofused Sorbolac and magnesium 1.496 9.112 stearate (98:2)(60 mins) Mechanofused Sorbolac and magnesium 2.028 8.281 stearate(95:5) (0 mins) Mechanofused Sorbolac and magnesium 0.961 8.551 stearate(95:5) (60 mins) Extra fine lactose 0.798 16.523 Mechanofused Extra finelactose (60 mins) 0.714 18.139 Mechanofused Extra fine lactose and 1.19517.703 magnesium stearate (98:2) (60 mins) Cyclomixed Sorbolac (60 mins)1.629 7.894 Cyclomixed Sorbolac and magnesium stearate 1.617 (98:2) (0mins) Cyclomixed Sorbolac and magnesium stearate 1.473 (98:2) (5 mins)Cyclomixed Sorbolac and magnesium stearate 1.442 (98:2) (10 mins)Cyclomixed Sorbolac and magnesium stearate 1.383 (98:2) (20 mins)Cyclomixed Sorbolac and magnesium stearate 1.404 (98:2) (40 mins)Cyclomixed Sorbolac and magnesium stearate 1.425 (98:2) (60 mins)Cyclomixed Sorbolac and magnesium stearate 1.779 (95:5) (0 mins)

Whilst the surface area does decrease as the processing time increased,this can probably be explained as being due to the magnesium stearatebecoming smeared over the surface.

Hosokawa Powder Tester

This system measures several different parameters, including: angle ofrepose; aerated bulk density; packed bulk density; angle of spatulabefore and after impact; angle of fall; and dispersibility.

The system then calculates further parameters/indices, including: angleof difference (repose−fall); compressibility (Cans index); average angleof spatula; and uniformity (based on d₁₀ and d₆₀).

Various powders were tested using this system and the resulting data aresummarised in Tables 1 to 5, shown in FIGS. 2 to 6 respectively.

As can be seen from the data, on processing with magnesium stearate (MgSt), virtually all of the powders showed a tendency to decrease theangle of repose and the angle of fall, and to increase in bulk densityand dispersibility.

For the Sorbolac 400 and the ultra-fine lactose, which are within thesize range considered suitable for use as the carrier according to thepresent invention, the powders mechnofused with magnesium stearate showvery considerable drops in the angle of repose and the angle of fall, aswell as increases in aerated bulk, compared to the raw material (seeTables 1 and 2). Where the powder is mixed using a low shear mix, inthis study a Turbula mixer was used, none of these changes are observed(see Table 1).

Table 3 shows Sorbolac 400 Cyclomixed with magnesium stearate. In theseexamples, considerable drops in the angle of repose and the angle offall are observed, as well as increases in aerated bulk density.However, these changes are generally slightly less than those observedwhen the Sorbolac 400 and magnesium stearate are mechanofused. This isconsistent with the increasing intensity of the processing methodsproducing increasing levels of effect.

Table 4 shows micronised lactose, which in these tests is used torepresent a model micronised drug. Unfortunately, the variability of theresults was higher and the data provided, especially for the angle ofrepose, the angle of fall for the raw material, was regarded asunreliable. The density increased but was still relatively low. Thesepowders were observed as being highly cohesive. Even after Mechanofusiononly slight improvements were seen, in contrast to the dramatic visiblepowder changes for Sorbolac 400 and the ultra-fine lactose.

Table 5 shows SV003, a traditional large lactose carrier material. Inthis case, the powder mechanofused with magnesium stearate shows smallerdrops in the angle of repose and no change in the angle of fall (whereit remains at an already low level in its original state). Similarly,the aerated bulk density increased slightly, but from an already highlevel.

Thus, the results indicate that the co-milled carrier particles withinthe preferred size range for the present invention and co-milled modeldrug particles showed a tendency to decrease in angle of repose, toincrease in bulk density and to increase in dispersibility. Theseproperties would be anticipated in conjunction with reduced cohesion.This improvement was observed to increase with increasing intensity ofthe co-milling methods and with increasing levels of additive material(magnesium stearate). The result is an improvement in performance of aformulation containing this carrier in an inhaler, in terms of improvedemitted dose and in terms of improved fine particle dose, especially thefine particle dose of metered dose.

The metered dose (MD) of a dry powder formulation is the total mass ofactive agent present in the metered form presented by the inhaler devicein question. For example, the MD might be the mass of active agentpresent in a capsule for a Cyclohaler™, or in a foil blister in aGyrohaler™ device.

The emitted dose (ED) is the total mass of the active agent emitted fromthe device following actuation. It does not include the material left onthe internal or external surfaces of the device, or in the meteringsystem including, for example, the capsule or blister. The ED ismeasured by collecting the total emitted mass from the device in anapparatus frequently identified as a dose uniformity sampling apparatus(DUSA), and recovering this by a validated quantitative wet chemicalassay (a gravimetric method is possible, but this is less precise).

The fine particle dose (FPD) is the total mass of active agent which isemitted from the device following actuation which is present in anaerodynamic particle size smaller than a defined limit. This limit isgenerally taken to be 5 μm if not expressly stated to be an alternativelimit, such as 3 μm, 2 μm or 1 μm, etc. The FPD is measured using animpactor or impinger, such as a twin stage impinger (TSI), multi-stageimpinger (MSI), Andersen Cascade Impactor (ACI) or a Next GenerationImpactor (NGI). Each impactor or impinger has a pre-determinedaerodynamic particle size collection cut points for each stage. The FPDvalue is obtained by interpretation of the stage-by-stage active agentrecovery quantified by a validated quantitative wet chemical assay (agravimetric method is possible, but this is less precise) where either asimple stage cut is used to determine FPD or a more complex mathematicalinterpolation of the stage-by-stage deposition is used.

The fine particle fraction (FPF) is normally defined as the FPD dividedby the ED and expressed as a percentage. Herein, the FPF of ED isreferred to as FPF(ED) and is calculated as FPF(ED)=(FPD/ED)×100%.

The fine particle fraction (FPF) may also be defined as the FPD dividedby the MD and expressed as a percentage. Herein, the FPF of MD isreferred to as FPF(MD), and is calculated as FPF(MD)=(FPD/MD)×100%.

Flodex Measurement

A means of assessing powder flow is to use the Flodex™ powder tester(Hansen Research).

The Flodex provides an index, over a scale of 4 to 40 mm, of flowabilityof powders. The analysis may be conducted by placing 50 g of aformulation into the holding chamber of the Flodex via a funnel,allowing the formulation to stand for 1 minutes, and then releasing thetrap door of the Flodex to open an orifice at the base of the holdingchamber. Orifice diameters of 4 to 34 mm can be used to measure theindex of flowability. The flowability of a given formulation isdetermined as the smallest orifice diameter through which flow of theformulation is smooth.

Carr's Index

A formulation may be characterised by its density/flowability parametersand uniformity of distribution of the active ingredient. The apparentvolume and apparent density can be tested according to the methoddescribed in the European Pharmacopoeia (Eur. Ph.).

Powder mixtures (100 g) are poured into a glass graduated cylinder andthe unsettled apparent volume V₀ is read; the apparent density beforesettling (dv) was calculated dividing the weight of the sample by thevolume V₀. After 1250 taps with the described apparatus, the apparentvolume after settling (V₁₂₅₀) is read and the apparent density aftersettling (ds) was calculated. The flowability properties were testedaccording to the method described in the Eur. Ph.

Powder mixtures (about 110 g) are then poured into a dry funnel equippedwith an orifice of suitable diameter that is blocked by suitable means.The bottom opening of the funnel is unblocked and the time needed forthe entire sample to flow out of the funnel recorded. The flowability isexpressed in seconds and tenths of seconds related to 100 g of sample.

The flowability can also be evaluated from the Carr's index calculatedaccording to the following formula: Carr's index (%)=((ds−dv)/ds)×100

A Carr index of less than 25 is usually considered indicative of goodflowability characteristics.

The uniformity of distribution of the active ingredient may be evaluatedby withdrawing 10 samples, each equivalent to about a single dose, fromdifferent parts of the blend. The amount of active ingredient of eachsample can be determined by High-Performance Liquid Chromatography(HPLC).

Determination of the Aerosol Performances

An amount of powder for inhalation may be tested by loading it into adry powder inhaler and firing the dose into an impactor or impinger,using the methods as defined in the European or US Pharmacopoeias.

SEM

This is a potentially useful method which may be used to identifypowders exhibiting low cohesion, large magnesium stearate agglomerates,and changes in surface morphology following processing and/orsegregation.

Differential Scanning Calorimetry (DSC) & Inverse Gas Chromatography(IGC)

These techniques may be useful for quantifying the surface energy andproduction of amorphous material during the processing of the powderparticles. Amorphous material is regarded as potentially harmful to thelong-term stability of powder formulations, making them prone torecrystallisation.

Powder characterisation parameters such as flowability indices or formsof surface characterisation have been considered. The Hosokawa PowderTester provided a good test to qualify changes in powder properties. Themechanofused powders showed a tendency to decrease in angle of repose,increase in bulk density and increase in dispersibility. However, as theparticles approach the micron size, these Hosokawa Powder Tester testswere less equivocal. Also, these parameters may not be directly linkedto performance during aerosolisation.

As well as characterizing the drug and fine carrier component powders,these Hosokawa Powder Tester tests are also helpful in characterizingthe final combined formulation, where the final formulation propertiesare advantageously similar to the properties of the co-milled finecarrier. Consequently, the combined formulation will have good flowproperties and provide low device retention.

Further, the good dispersibility of the drug component is retained,providing high levels of fine particle fraction and fine particle dose,as measured by standard in vitro tests. Such improvements are alsoconsistent, providing less variability in the test results obtained thanfor traditional formulation approaches.

Another very important advantage of the system of the present inventionis the consistency of the high performance. One of the many benefits ofconsistency is that it can also lead to reduction in adverse sideeffects experienced, as it will allow one to administer a smaller totaldose than is possible when relying upon conventional levels of inhalerefficiency or other routes of administration. In particular, it allowsone to target specific dosing windows wherein the therapeutic effect ismaximised whilst causing the minimum side effects.

According to a second aspect of the present invention, formulationswhich are obtainable by the methods according to the first aspect of theinvention are provided.

In powder compositions of the present invention, at least some of thecomposite particles may be in the form of agglomerates, preferablyunstable agglomerates. However, when the composite active particles areincluded in a pharmaceutical composition, the additive material promotesthe dispersal of the composite active particles on administration ofthat composition to a patient, via actuation of an inhaler. In theturbulence created upon actuation of the inhaler device, theagglomerates break up, releasing the composite particles of respirablesize.

The powder particles according to the present invention, which may beprepared as described herein, are not “low density” particles, as tendto be favoured in the prior art. Such low density particles can bedifficult and expensive to prepare. Indeed, previously, those skilled inthe art have only reported high performance in connection with powderparticles that have been prepared using fancy processing techniques suchas complex spray drying, which result in low density particles. Incontrast, the particles of the present invention are made using verysimple and economical processes.

In contrast to the suggestion in the prior art, it may be advantageousnot to produce severely dimpled or wrinkled particles as these can yieldlow density powders, with very high voidage between particles. Suchpowders have been reported as having good flow and dispersioncharacteristics, but they occupy a large volume relative to their massas a consequence of their shape and can result in packaging problems,i.e. require much larger blisters or capsules to hold a given mass ofpowder.

In one embodiment of the present invention, the powders have a tappeddensity of at least 0.1 g/cc, at least 0.2 g/cc, at least 0.3 g/cc, atleast 0.4 g/cc or at least 0.5 g/cc.

Example 11 Surface Chemical Analysis of Powders

The aim of the analysis is to identify the presence of magnesiumstearate on the surface of a model co-micronised powder. The modelpowders were processed in two different ways, with one representing aconventional pharmaceutical blending process, and the other being theintensive Mechanofusion process which is the subject of the invention.The aim was to show the contrast in surface coating efficiency. In thiscase the model material was micronised lactose, which could represent amicronised drug or a fine carrier.

The powders have been analyzed using both TOF-SIMS and XPS. TOF-SIMSprovides a mass spectrum of the outermost 1 nm of the surface, and isused here to assess whether the magnesium stearate coverage of thelactose is complete or in patches. XPS provides a spectrumrepresentative of the outermost 10 nm of the surface of the sample andis used here in comparison to the TOF-SIMS data to assess the depth ofcoverage of the magnesium stearate on the lactose surface.

In addition, the powders were studied using the Zetasizer 3000HSinstrument (Malvern Instruments Ltd, UK.) Each sample was tested incyclohexane, and zeta potential measurements were obtained.

The following powder samples were prepared for testing:

-   -   Lactose;    -   Lactose/Magnesium Stearate 19/1 mixed by Turbula mixer; and    -   Lactose/Magnesium Stearate 19/1 mixed by Mechanofusion.

TOF-SIMS

SIMS is a qualitative surface analytical technique that is capable ofproducing a high-resolution mass spectrum of the outermost 1 nm of asurface.

In brief, the SIMS process involves bombarding the sample surface with abeam of primary ions (for example caesium or gallium). Collision ofthese ions with atoms and molecules in the surface results in thetransfer of energy to them, causing their emission from the surface. Thetypes of particles emitted from the surface include positive andnegative ions (termed secondary ions), neutral species and electrons.Only secondary ions are measured in SIMS. Depending on the type of biasapplied to the sample, either positive or negative ions are directedtowards a mass spectrometer. These ions are then analysed in terms oftheir mass-to-charge ratio (m/

) yielding a positive or negative ion mass spectrum of counts detectedversus m/

. Different fragments will be diagnostic of different components of thesurface. TOF-SIMS is an advanced technique that has increasedsensitivity (<<parts per million (ppm) sensitivity), mass resolution andmass range compared to conventional SIMS techniques. SIMS operating instatic mode was used to determine the chemical composition of the topmonolayer of the surface. Under static SIMS conditions, the primary iondose is limited so that statistically the sample area analysed by therastered ion beam is exposed to the beam once only, and that thespectrum generated is representative of a pristine surface.

TOF-SIMS analysis of the Turbula mixed sample (Lactose/MagnesiumStearate 19/1 mixed by Turbula) indicated the presence of both lactoseand magnesium stearate in both positive and negative mass spectra, asshown in the table below. The presence of lactose in the spectraindicates that the surface coverage of magnesium stearate is incomplete.

TOF-SIMS analysis of the Mechanofusion mixed sample (Lactose/MagnesiumStearate 19/1 co-milled by Mechanofusion) also indicated the presence ofboth lactose and magnesium stearate in both positive and negative massspectra. The presence of lactose in the spectra indicates that thesurface coverage of magnesium stearate is incomplete.

It is important to note that SIMS spectra are not quantitative and sothe intensities of the peaks cannot be taken to reflect the degree ofsurface coverage.

XPS

XPS is a surface analytical technique that can quantify the amount ofdifferent chemical species in the outermost 10 nm of a surface. In thesimplest form of analysis, XPS measures the relative amount of eachelement present. Quantitative elemental identification can be achieveddown to 1 atom in 1000. All elements present can be detected with theexception of hydrogen. Elemental analysis may be essential indetermining the amount of a surface contaminant or to quantify anysurface species with a unique elemental type.

Relative Atomic Percentage Composition (%) Sample C O Mg LactoseMeasurement 1 54.47 45.43 Nd* Measurement 2 55.29 44.71 Nd* Mean 54.945.1 <0.1 Lactose/Magnesium Stearate (Turbula) Measurement 1 61.23 38.000.44 Measurement 2 60.40 39.02 0.50 Mean 60.8 38.5 0.5 Lactose/MagnesiumStearate (Mechanofusion) Measurement 1 81.39 17.07 1.51 Measurement 280.72 17.80 1.49 Mean 81.1 17.4 1.5 *Nd = not detected (<0.1 atomic %)

XPS analysis of the Lactose/Magnesium Stearate 19/1 sample mixed byTurbula revealed the presence of magnesium on the surface of the lactoseindicating the presence of magnesium stearate. Using the percentagepresence of magnesium on the surface it is calculated that the magnesiumstearate contributes 20% of the overall signal from the outermost 10 nmof the sample surface. Peak fitting the carbon 1s envelope enables theidentification and quantification of the functionalities present at thesurface. The clear increase in C—H/C—C carbon centres at the surface isascribed to the coverage of magnesium stearate and demonstrates asimilar degree of signal intensity to that predicted from the magnesiumabundance.

XPS analysis of the Lactose/Magnesium Stearate 19/1 Mechanofusion mixedsample again demonstrates the presence of magnesium stearate on thelactose surface by both the magnesium abundance and the increase inC—C/C—H functionality over that seen on pure lactose. Using thepercentage of magnesium in the spectrum the magnesium stearate iscalculated to contribute 61.5% of the signal from the outermost 10 nm ofthe sample surface. An increase of similar magnitude is observed for theC—C/C—H coverage.

The carboxyl functionality present on the surface of the lactose canmost likely be attributed to surface contamination, and as such thecarboxyl group is not used to assess the degree of magnesium stearatecoverage. However for the two mixed samples the extent of carboxylfunctionality follows the same trend as for magnesium and the C—C/C—Hincreases.

The Mechanofusion mixed sample demonstrated significantly increasedamounts of magnesium stearate at the surface, over the Turbula mixedsample. These differences could reflect either a thickening of thecoverage of magnesium stearate or an increased surface coverage giventhe incomplete coverage as demonstrated by TOF-SIMS analysis.

Area % of C 1 s Spectral Envelope Sample C—C C—O O—C—O O—C═O LactoseMeasurement 1 6.4 70.9 18.0 4.7 Measurement 2 4.4 57.8 22.0 12.8 Mean5.5 64.3 20.0 8.7 Lactose/Magnesium Stearate (Turbula) Measurement 125.8 57.5 14.7 2.1 Measurement 2 24.7 58.8 15.0 1.6 Mean 25.2 58.1 14.81.8 Lactose/Magnesium Stearate (Mechanofusion) Measurement 1 75.7 16.13.9 4.3 Measurement 2 73.9 17.2 4.5 4.5 Mean 74.8 16.6 4.2 4.4

In conclusion both mixed samples demonstrate an incomplete coverage ofmagnesium stearate, but with about three times more magnesium stearatepresent on the Mechanofusion mixed sample than the Turbula sample in thetop 10 nm of the surface.

Zeta Potential

Zetasizer measures the zeta potential. This is a measure of the electricpotential on a particle in suspension in the hydrodynamic plane ofshear. The results are summarized as follows:

Zeta Sample Potential (mV) Lactose 35.5 Lactose/Magnesium Stearate 4.8(19/1) (Turbula) Lactose/Magnesium Stearate −34.8 (19/1) (Mechanofusion)

Each result is an average of 10 measurements. The data are presented inFIG. 7. This technique shows a clear difference in the zeta potentialmeasurements, as a function of surface coating process, where theimproved covering of magnesium stearate is indicated by an increasinglynegative zeta potential.

These results demonstrate that applying the additive material to fine orultra-fine carrier or active particles by conventional mixing orblending, for example using a low shear mixer like a Turbula mixer, doesnot provide the same improvement in powder performance as the use of theco-milling process according to the present invention. The latterprocesses appear to literally fuse the additive material to the surfacesof the active or carrier particles.

The powders of the present invention are extremely flexible andtherefore have a wide number of applications, for both local applicationof drugs in the lungs and for systemic delivery of drugs via the lungs.

The present invention is also applicable to nasal delivery, and powderformulations intended for this alternative mode of administration to thenasal mucosa.

The formulations according to the present invention may be administeredusing active or passive devices, as it has now been identified how onemay tailor the formulation to the device used to dispense it, whichmeans that the perceived disadvantages of passive devices where highperformance is sought may be overcome.

According to a third aspect of the present invention, a dry powderdevice is provided, the device comprising a powder formulation accordingto the second aspect of the invention.

In one embodiment of the invention, the inhaler device is an activedevice, in which a source of compressed gas or alternative energy sourceis used. Examples of suitable active devices include Aspirair™ (VecturaLtd) and the active inhaler device produced by Nektar Therapeutics (ascovered by U.S. Pat. No. 6,257,233).

In an alternative embodiment, the inhaler device is a passive device, inwhich the patient's breath is the only source of gas which provides amotive force in the device. Examples of “passive” dry powder inhalerdevices include the Rotahaler™ and Diskhaler™ (GlaxoSmithKline) and theTurbohaler™ (Astra-Draco) and Novolizer™ (Viatris GmbH).

The size of the doses can vary from micrograms to tens of milligrams.The fact that dense particles may be used, in contrast to conventionalthinking, means that larger doses can be administered without needing toadminister large volumes of powder and the problems associatedtherewith.

The dry powder formulations may be pre-metered and kept in foil blisterswhich offer chemical and physical protection whilst not beingdetrimental to the overall performance. Indeed, the formulations thuspackaged tend to be stable over long periods of time, which is verybeneficial, especially from a commercial and economic point of view.

According to a fourth aspect of the present invention, a receptacle isprovided, holding a single dose of a powder according to the secondaspect of the present invention.

The receptacle may be a capsule or blister, preferably a foil blister.

1-21. (canceled)
 22. A powder formulation comprising an active,magnesium stearate and lactose, wherein the powder formulationincorporates magnesium stearate on the surface of both the activeparticles and the lactose particles, and wherein when the magnesiumstearate is added to the lactose, the amount used is from 0.5 to 2% w/w.23. A powder formulation according to claim 22, the formulation beingobtainable by co-milling of active particles with magnesium stearate,separately co-milling lactose particles with magnesium stearate, andcombining the co-milled active and co-milled lactose particles.
 24. Apowder formulation according to claim 22 wherein magnesium stearateforms a discontinuous coating on the surfaces of the active and lactoseparticles.
 25. A powder formulation according to claim 23 whereinmagnesium stearate forms a discontinuous coating on the surfaces of theactive and lactose particles.
 26. A powder formulation according toclaim 22 wherein the powder formulation has a tapped density of at least0.1 g/cc.
 27. A powder formulation according to claim 25 wherein thepowder formulation has a tapped density of at least 0.1 g/cc.
 28. Apowder formulation according to claim 22 wherein the active is abronchodilator, such as a β₂ agonist.
 29. A powder formulation accordingto claim 22 which is a passive device powder formulation.
 30. A drypowder inhaler device comprising a powder formulation according to claim22 wherein the device is a passive device.
 31. A dry powder inhalerdevice comprising a powder formulation according to claim 23 wherein thedevice is a passive device.
 32. A dry powder inhaler device comprising apowder formulation according to claim 24 wherein the device is a passivedevice.
 33. A dry powder inhaler device comprising a powder formulationaccording to claim 25 wherein the device is a passive device.
 34. A drypowder inhaler device comprising a powder formulation according toclaims 26 wherein the device is a passive device.
 35. A dry powderinhaler device comprising a powder formulation according to claim 27wherein the device is a passive device.
 36. A dry powder inhaler devicecomprising a powder formulation according to claim 28 wherein the deviceis a passive device.
 37. A dry powder inhaler device comprising a powderformulation according to claim 29 wherein the device is a passivedevice.